Sensor with layered electrodes

ABSTRACT

A thin film sensor, such as a glucose sensor, is provided for transcutaneous placement at a selected site within the body of a patient. The sensor includes several sensor layers that include conductive layers and includes a proximal segment defining conductive contacts adapted for electrical connection to a suitable monitor, and a distal segment with sensor electrodes for transcutaneous placement. The sensor electrode layers are disposed generally above each other, for example with the reference electrode above the working electrode and the working electrode above the counter electrode. The electrode layers are separated by dielectric layer.

RELATED APPLICATION DATA

This is a continuation of U.S. patent application Ser. No. 12/229,206,filed Aug. 20, 2008, now U.S. Pat. No. ______, which is a divisional ofU.S. patent application Ser. No. 11/234,523, filed Sep. 23, 2005, nowU.S. Pat. No. 7,725,148, all of which are incorporated herein byreference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates generally to a sensor and methods formanufacturing a sensor for placement at a selected site within the bodyof a patient. More specifically, this invention relates to thepositioning of electrodes in an improved flexible thin film sensor ofthe type used, for example, to obtain periodic blood glucose (BG)readings.

2. Description of Related Art

Thin film electrochemical sensors are generally known in the art for usein a variety of specialized sensor applications. Such thin film sensorsgenerally comprise one or more thin conductors applied byphotolithography mask and etch techniques between thin layers of anonconductive film material, such as polyimide film. The conductors areshaped to define distal segment ends having an appropriate electrodematerial thereon, in combination with proximal end contact pads adaptedfor conductive connection with appropriate electronic monitoringequipment. In recent years, thin film sensors of this general type havebeen proposed for use as a transcutaneous sensor in medicalapplications. As one example, thin film sensors have been designed foruse in obtaining an indication of BG levels and monitoring BG levels ina diabetic patient, with the distal segment portion of the electrodespositioned subcutaneously in direct contact with patient blood. Suchreadings can be especially useful in adjusting a treatment regimen whichtypically includes regular administration of insulin to the patient. Inthis regard, BG readings are particularly useful in conjunction withsemiautomated medication infusion pumps of the external type, asgenerally described in U.S. Pat. Nos. 4,562,751; 4,678,408; and4,685,903; or automated implantable medication infusion pumps, asgenerally described in U.S. Pat. No. 4,573,994.

Relatively small and flexible electrochemical sensors have beendeveloped for subcutaneous placement of sensor electrodes in directcontact with patient blood or other extracellular fluid, wherein suchsensors can be used to obtain periodic readings over an extended periodof time. In one form, flexible transcutaneous sensors are constructed inaccordance with thin film mask techniques wherein an elongated sensorincludes thin film conductive elements encased between flexibleinsulative layers of polyimide sheet or similar material. Such thin filmsensors typically include exposed electrodes at a distal segment fortranscutaneous placement in direct contact with patient blood or thelike, and exposed conductive contacts at an externally located proximalsegment end for convenient electrical connection with a suitable monitordevice. Such thin film sensors hold significant promise in patientmonitoring applications, but unfortunately have been difficult to placetranscutaneously with the sensor electrodes in direct contact withpatient blood or other extracellular fluid. Improved thin film sensorsand related insertion sets are described in commonly assigned U.S. Pat.Nos. 5,299,571, 5,390,671; 5,391,250; 5,482,473; 5,568,806; and5,586,553 and International Publication No. WO 2004/036183, which areincorporated by reference herein.

BRIEF SUMMARY OF THE INVENTION

The present invention relates specifically to an improved sensor adaptedto have a thin configuration for quick and easy placement of the filmsensor on a patient with sensor electrodes in direct contact withpatient blood or other extracellular fluid.

In accordance with embodiments of the invention, a sensor, such as aflexible thin film electrochemical sensor, is provided that may beplaced at a selected site within the body of the patient. In certainembodiments, the sensor includes several electrodes, configured so thatthe overall size of the sensor is thinner than traditional sensors. Inan embodiment of the present invention, the sensor includes electrodesin electrode layers positioned generally above each other. Theelectrodes and traces from the electrodes to contact pads, which areadapted to connect to sensor electronics, may be horizontally displacedfrom each other with other materials layered in between. The electrodesthemselves may be in a staggered configuration so that the lowerelectrodes extend further, allowing portions of the electrodes to beexposed. Each of the electrodes may also be of the same size ordifferent sizes. In the layered configuration, the electrode layers arestaggered to expose a part of each electrode to contact the patientfluid.

In further embodiments of the invention, the electrodes may include aworking electrode and a counter electrode and may further include areference electrode. Alternatively, the electrodes may include more orfewer electrodes, depending on the desired use. The electrodes maycomprise gold and chrome and/or other adhesive/conductive layers, suchas titanium, platinum, tungsten, etc. The working and counter electrodesmay be plated with platinum black and the reference electrode may beplated with silver and silver chloride. For glucose sensing, the sensormay include a layer of glucose oxidase, which may be mixed with albumin.Over the glucose oxidase may be a glucose limiting membrane, such as onethat includes a polyamine, such as polyoxypropylene-diamine sold underthe trademark JEFFAMINE®, and polydimethylsiloxane. There may be ahydrophilic membrane over the glucose limiting membrane.

In an embodiment of the invention, a subcutaneous insertion set isprovided for placing the sensor at a selected site within the body of apatient. The insertion set comprises the sensor and further comprises aslotted insertion needle extending through a mounting base adapted forseated mounting onto the patient's skin. The flexible thin film sensorincludes a proximal segment carried by the mounting base, and a distalsegment protruding from the mounting base and having one or more sensorelectrodes thereon. The distal segment of the sensor is carried within aprotective cannula which extends from the mounting base with a portionof the cannula being slidably received within the insertion needle. Oneor more apertures foimed in the cannula are positioned in generalalignment with the staggered sensor electrodes on the sensor distalsegment.

In embodiments of the invention, when the mounting base is pressed ontothe patient's skin, the insertion needle pierces the skin totranscutaneously place the cannula with the sensor distal segmenttherein. The insertion needle can be withdrawn from the mounting base,leaving the cannula and sensor distal segment within the patient, withthe sensors electrodes thereon exposed through the aperture or aperturesfor direct contact with to patient fluid at the selected position withinthe patient, such as a subcutaneous, intravascular, intramuscular, orintravenous site. Other sites may include intraorgan and interperitonealsites. Conductive contacts on the sensor proximal segment end can beelectrically connected to a suitable monitor device so that appropriateblood chemistry readings can be taken.

In further embodiments of the invention, during insertion, the insertionneedle and the protective cannula cooperatively protect and guide thesensor to the desired transcutaneous placement position. The insertionneedle can then be withdrawn, whereupon the slotted needle geometrypermits the insertion needle to slide over and longitudinally separatefrom the second portion of the cannula, thereby leaving the cannula andsensor therein at the selected insertion site.

Other features and advantages of the present invention will become moreapparent from the following detailed description, taken in conjunctionwith the accompanying drawings which illustrate, by way of example, theprinciples of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

A detailed description of embodiments of the invention will be made withreference to the accompanying drawings, wherein like numerals designatecorresponding parts in the figures.

FIG. 1 a is an enlarged fragmented sectional view of a sensor accordingto an embodiment of the invention;

FIG. 1 b is an enlarged fragmented sectional view correspondinggenerally with a first and second electrode layer of a sensor accordingto an embodiment of the invention;

FIG. 1 c is an enlarged fragmented sectional view correspondinggenerally with a first, second, and third electrode layer of a sensoraccording to an embodiment of the invention;

FIG. 2 is an enlarged side view of a sensor according to an embodimentof the invention;

FIG. 3 is an enlarged cross-sectional view taken generally on the line2-2 of FIG. 1 c;

FIG. 4 is an enlarged cross-sectional view taken generally on the line3-3 of FIG. 1 c;

FIG. 5 is a perspective view illustrating a transcutaneous sensorinsertion set according to an embodiment of the invention;

FIG. 6 is an enlarged longitudinal vertical section taken generally onthe line 2-2 of FIG. 5 according to an embodiment of the invention;

FIG. 7 is an exploded perspective view illustrating a plurality of thinfilm electrochemical sensors formed on a rigid flat substrate accordingto an embodiment of the invention.

DETAILED DESCRIPTION

In the following description, reference is made to the accompanyingdrawings which form a part hereof and which illustrate severalembodiments of the present inventions. It is understood that otherembodiments may be utilized and structural and operational changes maybe made without departing from the scope of the present inventions.

In embodiments of the present invention, a method is provided forproducing electrochemical sensors of the type used, for example, insubcutaneous or transcutaneous monitoring of analytes in a patient. Forexample, they may be used for monitoring of blood glucose levels in adiabetic patient. The sensors of the invention may also be used forsensing other analytes, such as lactate. While certain embodiments ofthe invention pertain to glucose sensors, the structure of the sensordisclosed and methods of creating the sensor can be adapted for use withany one of the wide variety of sensors known in the art. A number ofenzyme sensors (e.g., glucose sensors that use the enzyme glucoseoxidase to effect a reaction of glucose and oxygen) are known in theart. See, for example, U.S. Pat. Nos. 5,165,407, 4,890,620, 5,390,671and 5,391,250, and International Publication No. WO 2004/036183, whichare herein incorporated by reference. Sensors for monitoring glucoseconcentration of diabetics are further described in Schichiri, et al.,“In Vivo Characteristics of Needle-Type Glucose Sensor-Measurements ofSubcutaneous Glucose Concentrations in Human Volunteers,” Horm. Metab.Res., Suppl. Ser. 20:17-20 (1988); Bruckel, et al., “In Vivo Measurementof Subcutaneous Glucose Concentrations with an Enzymatic Glucose Sensorand a Wick Method,” Klin. Wochenschr. 67:491-495 (1989); and Pickup, etal., “In Vivo Molecular Sensing in Diabetes Mellitus: An ImplantableGlucose Sensor with direct Electron Transfer,” Diabetologia 32:213-217(1989), which are herein incorporated by reference. Other sensors aredescribed, for example, in Reach, et al., ADVANCES IN IMPLANTABLEDEVICES, A. Turner (ed.), JAI Press, London, Chap. 1, (1993), which isherein incorporated by reference.

The electrochemical sensors of embodiments of the invention are filmsensors that include several electrodes, configured so that the overallsize of the sensor is thinner than traditional sensors. In furtherembodiments of the present invention, the sensor includes threeelectrodes that are each positioned generally above the other, althoughthe term “above” is intended to mean generally disposed in a planevertically on top of each other, not necessarily directly over ordisposed on one another. For example, the electrodes may be above andadjacent to another electrode, such as offset horizontally. The sensorof the invention may have only two electrodes or more than threeelectrodes. In an embodiment with three electrodes, each of the threeelectrodes may be of the same size or different sizes. In particularembodiments, the electrode layers are staggered to expose at least aportion of each electrode to contact the patient fluid. The three sensorelectrodes may all serve different functions. For example, there may bea working electrode, a counter electrode, and a reference electrode. Thereference electrode facilitates the filtering out of background chemicalreactions that could detract from a correct reading of the BG level. Inbetween layers of the sensor electrodes, a layer of insulation ordielectric material may be spread so that there is no communicationbetween the individual electrodes.

The exposed portions of the electrodes are coated with a thin layer ofmaterial having an appropriate chemistry. For example, an enzyme such asglucose oxidase, glucose dehydrogenase, or hexokinase can be disposed onthe exposed portion of the sensor element within an opening or aperturedefined in a cover layer.

FIGS. 1 a-c illustrate longitudinal cross-sections of an embodiment ofthe invention where the various layers of the distal end 16 of thesensor 12 (shown in FIG. 2), specifically the sensor layers 64 a, 64 b,and 64 c, are shown. In the illustrated embodiment, there are threemetallization steps taken to form the electrodes 18 a, 18 b, and 18 c.The metallization process forms one or more conductive layers/electrodelayers 54 a, 54 b, and 54 c on top of a base layer 42. The base layer 42is generally an electrically insulating layer such as a polyimidesubstrate, which may be self-supporting or further supported by anothermaterial. In one embodiment, the base layer 42 comprises a polyimidetape, dispensed from a reel. Providing the base layer 42 in this formcan facilitate clean, high density mass production. Further, in someproduction processes using such a polyimide tape, sensors can beproduced on both sides of a tape.

FIG. 2 illustrates an enlarged fragmented sectional view of a sensoraccording to an embodiment of the invention. The electrodes 18 a, 18 b,and 18 c at the distal end 16 of the sensor 12 lead through traces 48 a,48 b, and 48 c to conductive pads 21 a, 21 b, and 21 c at a proximal end20 of the sensor. Although the figures and the description belowdescribes the formation and structure of a sensor with three electrodes,the method and structure can be used in a sensor of fewer or moreelectrodes.

The first metallization step, shown in FIG. 1 a, applies the conductivelayer 54 a onto the insulative base layer 42. The conductive layer maybe provided as a plurality of thin film conductive layers, such as aninitial chrome-based layer suitable for chemical adhesion to the baselayer, followed by subsequent formation of a thin film gold-based layer.Optionally, a chrome-based top layers may be formed on top of the thinfilm gold-based layer. The conductive layer may also be formed of goldand/or chrome in different ratios and/or other adhesive/conductivelayers, such as titanium, platinum, tungsten, etc. In alternativeembodiments, other electrode layer conformations or materials can beused. The conductive layer 54 a can be applied using electrodedeposition, surface sputtering or another suitable process step. Theelectrical circuit of each conductive layer typically comprises one ormore conductive paths with regions at a proximal end to form contactpads and regions at a distal end to form sensor electrodes. Generally,etching is performed to define the electrical circuit of each layer.Alternatively, “lift off” may be used, in which the photoresist definesa pattern prior to metal sputtering, after which the photoresist isdissolved away (along with the unwanted metal), and the metal pattern isleft behind. In further embodiments, photoresisting is performed toprotect the metallized trace and electrode and photoimaging is performedto cure specified areas. For example, the conductive layer is coveredwith a selected photoresist coating, followed by an etch step resultingin one or more conductive paths. An electrically insulative cover layer(or dielectric layer) 44 a, such as a polymer coating, is then appliedover at least portions of the conductive layer 54 a. Acceptable polymercoatings for use as the insulative cover layer 44 a include, forexample, non-toxic biocompatible polymers such as polyimide,biocompatible solder masks, epoxy acrylate copolymers, and the like.Further, these coatings can be photoimageable to facilitatephotolithographic forming of apertures through to the conductive layer54 a to expose the electrode 18 a. This first metallization step isfinished by developing and rinsing the produced electrode 18 a. In anembodiment this electrode 18 a is the counter electrode. Alternatively,the electrode 18 a may be a working or reference electrode.

The second metallization step, shown in FIG. 1 b, applies a secondconductive layer 54 b over the first insulative cover layer 44 a andcovering and repeats the process of covering the second conductive layer54 b with another insulative cover layer 44 b. This produces anotherelectrode 18 b, positioned generally above the first electrode 18 a. Inan embodiment, electrode 18 b is the working electrode. Alternatively,the electrode 18 b may be a counter or working electrode. The thirdmetallization step, shown in FIG. 1 c, repeats all of the previous stepsto form a third electrode 18 c. In an embodiment, electrode 18 c is thereference electrode. Alternatively, the electrode 18 c may be a workingor counter electrode. As shown in FIG. 1 c, the electrodes are in astaggered configuration, so that at least a portion of each electrodemay be exposed. The conductive layers 54 a, 54 b and 54 c, may bedirectly above each other or horizontally displaced from each other(into and out of the page). The electrodes may further be configured inany way that allows the electrodes to contact fluid when inserted into abody of a patient.

The sensor 12 is thus shown with the subsequent conductive layers 54 a,54 b, and 54 c alternating with the insulative layers 44 a, 44 b, and 44c. In between every two conductive layers there is an insulative layerthat serves to isolate each conductive layer so that there is no tracecommunication between the layers. Apertures 19 a, 19 b, and 19 c areformed in the top insulative cover layer 44 c. Although the electrodes18 a, 18 b, and 18 c are shown as lying on top of each other, it is alsopossible to have them generally above each other, but spaced sideways sothat they are not directly on top of each other (e.g., horizontallydisplaced). This is also true for the traces that lead to conductivecontacts, which electrically connect to the sensor electronics, at theopposite end of the sensor from the electrodes. The apertures can bemade through photolithographic development, laser ablation, chemicalmilling, etching, or the like. The exposed electrodes and/or contactpads can also undergo secondary processing through the apertures, suchas additional plating processing, to prepare the surfaces, and/orstrengthen the conductive regions.

As shown in FIG. 4, typically, a sensor chemistry layer 72 is disposedon one or more of the exposed electrodes (e.g., 18 a) of the conductivelayers. In certain embodiments, the sensor chemistry layer 72 is anenzyme layer, for example, glucose oxidase. If the enzyme layer isglucose oxidase, it reacts with glucose to produce hydrogen peroxide,which modulates a current to the electrode which can be monitored tomeasure an amount of glucose present. The sensor chemistry layer 72 canbe applied over portions of the sensor 12 or over the entire sensor,including the protective layer (e.g., 44 a). The sensor chemistry layer72 is generally disposed on at least portions of a working electrode. Infurther embodiments, the sensory chemistry layer may be disposed on atleast portions of other electrodes, such as a counter electrode. Forexample, if the electrode 18 a in FIG. 4 is the counter electrode, thenthe sensor chemistry layer 72 is disposed on at least portions of theelectrode 18 a. Example methods for generating the sensor chemistrylayer include spin coating processes, dip and dry processes, low shearspraying processes, ink-jet printing processes, silk screen processes,casting process, and the like.

In certain embodiments, the sensor chemistry layer 72 comprises glucoseoxidase and a carrier protein. The glucose oxidase and carrier proteinmay be in a substantially fixed ratio. In further embodiments, theglucose oxidase and the carrier protein are distributed in asubstantially uniform manner throughout the disposed enzyme layer.Typically, the carrier protein comprises albumin, generally in an amountof about 2-10% by weight, preferably about 5% by weight. As used herein,“albumin” refers to those albumin proteins typically used by artisans tostabilize polypeptide compositions, such as human serum albumin, bovineserum albumin, and the like. The application of the glucose oxidase andalbumin mixture may be made, for example, by a spin coating process, acasting process, a screen printing process or a doctor blading process.Optionally, the glucose oxidase layer that is formed on the sensor isless than 2 microns in thickness. In further embodiments, the glucoseoxidase layer may be less than 1, 0.5, 0.25 or 0.1 microns in thickness.The choice of the glucose oxidase layer thickness may be made to balancefast response and fast hydration verses a sensor lifetime. Generally,thin layers hydrate and respond more quickly, but do not last as long.Thick layers last a long time, but hydrate more slowly and respond toglucose more slowly.

The sensor chemistry layer 72 may be coated with one or more coverlayers. In certain embodiments, as shown in FIG. 4, the cover layer 74comprises a membrane that can regulate the amount of analyte that cancontact the enzyme of the sensor chemistry layer 72. For example, thecover layer 74 can comprise a glucose limiting membrane, which regulatesthe amount of glucose that contacts the glucose oxidase enzyme layer onan electrode. Such glucose limiting membranes can be made from a widevariety of materials suitable for such purposes, such as, for example,silicone, polyurethane, cellulose acetate, Nafion, polyester sulfonicacid (Kodak AQ), hydrogels, etc. In further embodiments the glucoselimiting membrane includes a polyamine, such as polyoxypropylene-diaminesold under the trademark JEFFAMINE®, and polydimethylsiloxane (StructureI) and/or a polysilane, such as polydimethylsiloxane (PDMS) (StructureII). In still further embodiments, the glucose limiting membrane is arandom block copolymer made from JEFFAMINE® and PDMS. In furtherembodiments, the glucose limiting membrane may also, or alternatively,be a mechanically limiting membrane. For example, a glucose limitingmembrane may be used that is an oxygen passing/glucose limiting polymer,such as silicone, and a small window with the correct ratio size may becut into the polymer to meter glucose directly to the sensor surface.

In still further embodiments, the JEFFAMINE®, which is glucosepermeable, and the PDMS, which is non-glucose permeable but oxygenpermeable, are linked together with diisocyanide. By using this randomblock copolymer, an excess of oxygen by the glucose oxidase and theelectrodes can be ensured along with a restricted amount of glucose.

In further embodiments, an adhesion promoter (not shown) is providedbetween the glucose limiting membrane 74 and the sensor chemistry layer72 to facilitate contact and/or adhesion. The adhesion promoter layercan be made from any one of a wide variety of materials that facilitatesbonding, for example materials comprising a silane compound, such as anaminopropyltriethoxy silane. Alternatively, protein or like molecules inthe sensor chemistry layer 72 can be sufficiently crosslinked orotherwise prepared to allow the glucose limiting membrane 74 to bedisposed in direct contact with the sensor chemistry layer in absence ofan adhesion promoter layer. The adhesion promoter layer can be spincoated, sprayed, cast, etc. onto the enzyme layer. It may be exposed toheat and humidity to create silanol (sticky) groups. In furtherembodiments, the layer may be repeated. Although not necessary, thecoating may help adhesion oxygen buffering. The time for exposure toheat and humidity is time sufficient to create silanol (sticky) groups,for example about two hours.

A hydrophilic membrane 76, which may be non-toxic and biocompatible, maybe positioned above the glucose limiting membrane 74. The hydrophilicmembrane 76 promotes tolerance of the sensor in the body.

Typically, the electrodes are formed by one of the variety of methodsknown in the art such as photoresist, etching and rinsing to define thegeometry of the active electrodes. The electrodes can then be madeelectrochemically active, for example by electrodeposition of platinumblack for the working and counter electrode, and silver followed bysilver chloride on the reference electrode. The sensor chemistry layeris then disposed on the conductive layer by a method other thanelectrochemical deposition, usually followed by vapor crosslinking, forexample with a dialdehyde, such as glutaraldehyde, or a carbodi-imide.

The electrodes and conductive layers are generally composed ofconductive materials. However, they are not limited to conductiveelements. Other useful sensor elements can be formed from any materialthat is capable of producing a detectable signal after interacting witha preselected analyte whose presence is to be detected. The detectablesignal can be, for example, an optically detectable change, such as acolor change or visible accumulation of the desired analyte (e.g.,cells). Exemplary such materials include polymers that bind specifictypes of cells, single-strand DNA, antigens, antibodies and reactivefragments thereof, etc. Sensor elements can also be formed frommaterials that are essentially non-reactive (i.e., controls). Theforegoing alternative sensor elements are beneficially included, forexample, in sensors for use in cell-sorting assays and assays for thepresence of pathogenic organisms, such as viruses (HIV, hepatitis-C,etc.), bacteria, protozoa, and the like.

As shown in FIGS. 2 and 3, in one embodiment of the present invention asensor 12 has the three electrodes 18 a, 18 b, and 18 c positionedgenerally one above the other. The three electrode layers comprise aplurality of elongated conductive traces 48 a, 48 b, and 48 c connectedto the electrodes 18 a, 18 b, and 18 c on one end and connected toconductive pads 21 a, 21 b, and 21 c on the opposing proximal segment20. Each electrode layer is formed between an underlying insulative baselayer 42 and an overlying insulative cover layer 44. Apertures (notshown) may be formed on the insulative cover layer 44 to expose thedistal segment 16 and the proximal segment 20 of the electrodes. In aglucose monitoring application, the flexible sensor 12 is placedtranscutaneously so that the distal segment 16 is in direct contact withpatient blood or extracellular fluid, and wherein the proximal segment20 is disposed externally for convenient connection, either by wired orwireless communication, to a monitoring device (not shown).

One or more sensors are formed on a rigid flat substrate, such as aglass plate or a ceramic. When finished, the sensors may be removed fromthe rigid flat substrate by a suitable method, such as laser cutting.Other materials that can be used for the substrate include, but are notlimited to, stainless steel, aluminum, and plastic materials. As seen inFIG. 7, the flexible sensors 12 a, 12 b, and 12 c are formed in a mannerwhich is compatible with photolithographic mask and etch techniques, butwhere the sensors 12 a, 12 b, and 12 c are not physically adhered orattached directly to the substrate 52. Each sensor comprises a pluralityof thin film electrodes 18 a, 18 b, and 18 c formed between anunderlying insulative base layer 42 and an insulative cover layer 44. Aplurality of elongated conductive traces 48 a, 48 b, and 48 c mayconnect the proximal segment end 20 to the distal segment end 16. At theproximal segment end 20, contact pads 21 a, 21 b, and 21 c are formed.Apertures (not shown) formed in the insulative cover layer expose thedistal end 16 portion of the electrodes 18 a, 18 b, and 18 c so thatthey are in direct contact with patient blood or extracellular fluid.

In one embodiment of a sensor set, shown in FIGS. 5 and 6, a flexibleelectrochemical sensor 12 is constructed according to so-called thinfilm mask techniques to include elongated thin film conductors embeddedor encased between layers of a selected insulative material such aspolyimide film or sheet. The sensor electrodes 18 (shown in exaggeratedform in the drawings) at a tip end of the sensor distal segment 16 areexposed through one of the insulative layers for direct contact withpatient fluids, such as blood and/or interstitial fluids, when thesensor is transcutaneously placed. FIG. 6 shows how the distal segment16 is joined to a proximal segment 20, the end of which terminates insuitable conductive contact pads or the like which are also exposedthrough one of the insulative layers. As illustrated schematically inFIG. 6, the proximal segment 20 and the contact pads thereon are adaptedfor electrical connection to a suitable monitor 22 for monitoringpatient condition in response to signals derived from the sensorelectrodes 18. The sensor electronics may be separated from the sensorby wire or be attached directly on the sensor. For example, the sensormay be housed in a sensor device including a housing that contains allof the sensor electronics, including any transmitter necessary totransmit data to a monitor or other device. The sensor devicealternatively may include two portions, one portion housing the sensorand the other portion housing the sensor electronics. The sensorelectronics portion could attach to the sensor portion in a side-to-sideor top-to-bottom configuration, or any other configuration that wouldconnect the two portions together. If the sensor electronics are in ahousing separated by a wire from the sensor, the sensor electronicshousing may be adapted to be placed onto the user's skin or placed onthe user's clothing in a convenient manner. The connection to themonitor 22 may be wired or wireless. In a wired connection, the sensorelectronics may essentially be included in the monitor instead of in ahousing with the sensor. Alternatively, sensor electronics may beincluded with the sensor as described above. A wire could connect thesensor electronics to the monitor. Examples of wireless connectioninclude, but are not limited to, radio frequency, infrared, WiFi, ZigBeeand Bluetooth. Additional wireless connections further include singlefrequency communication, spread spectrum communication, adaptivefrequency selection and frequency hopping communication. In furtherembodiments, some of the electronics may be housed on the sensor andother portions may be in a detachable device. For example, theelectronics that process and digitize the sensor signal may be with thesensor, while data storage, telemetry electronics, and any transmissionantenna may be housed separately. Other distributions of electronics arealso possible, and it is further possible to have duplicates ofelectronics in each portion. Additionally, a battery may be in one orboth portion. In further embodiments, the sensor electronics may includea minimal antenna to allow transmission of sensor data over a shortdistance to a separately located transmitter, which would transmit thedata over greater distances. For example, the antenna could have a rangeof up to 6 inches, while the transmitter sends the information to thedisplay, which could be over 10 feet away.

Further description of flexible thin film sensors of this general typemay be found in U.S. Pat. No. 5,482,473, which is incorporated byreference herein. The proximal segment 20 may be conveniently connectedelectrically to the monitor 22 by means of a connector block 24 as shownand described in U.S. Pat. No. 5,482,473, which is also incorporated byreference herein.

The overall sensor height of the sensor 12 (from base to top insulativelayer) may be about 0.001 inches or 25 microns. The base layer is about12 microns and each insulative layer is about 5 microns. Theconductive/electrode layers are each in the range of several thousandangstroms. Any of these layers could be thicker if desired. The overallwidth of the sensor is as small as about 150 microns. It could beslightly larger, about 250 microns or 0.010 inches. The width could alsolarger if desired. The length of the sensor is dependant on how deep thetissue is at the placement site. For example, for subcutaneous sensing,the sensor length may be about 0.50 inches to about 1.5 inches, forexample, about 1 inch.

The sensor 12 is carried by a mounting base 26 adapted for placementonto the skin of a patient. As shown, the mounting base 26 comprises anenlarged and generally rectangular pad having an underside surfacecoated with a suitable pressure sensitive adhesive layer, with apeel-off paper strip 28 normally provided to cover and protect theadhesive layer, until the insertion set 10 is ready for use. As shown inFIGS. 5 and 6, the mounting base comprises upper and lower layers 30 and32, with the proximal segment 20 of the flexible sensor 12 sandwichedbetween. The proximal sensor segment 20 has a forwardmost end joined tothe distal segment 16 which is folded angularly to extend downwardlythrough a slot 34 formed in the lower base layer 32.

The insertion needle 14 is adapted for slide-fit reception through aneedle port 36 formed in the upper base layer 30 and further through thelower slot 34 in the lower base layer 32. As shown in FIG. 5, theinsertion needle 14 has a sharpened tip 38 and an open slot 40 whichextends longitudinally from the tip 38 at the underside of the needle toa position at least within the slot 34 in the lower base layer 32. Abovethe mounting base 26, the insertion needle 14 may have a full roundcross sectional shape and is desirably closed at a rear end. In thepreferred embodiment, the slotted needle 14 has a part-circular crosssectional shape, with an arcuate dimension or span greater than 180degrees, such as on arcuate dimension of about 210 degrees. This leavesa longitudinal slot in the needle with an arcuate dimension of about 150degrees.

The cannula 15 is shown in FIG. 6 and comprises a part circular crosssection fitted within the insertion needle 14 to extend downwardly fromthe mounting base 26. This cannula 15 is constructed from a suitablemedical grade plastic or elastomer, such as polytetrafluoroethylene,silicone, or the like. The cannula 15 has one end fitted into the slot34 formed in the lower layer 32 of the mounting base 26, wherein thecannula 15 is desirably secured to the mounting base by a suitableadhesive or other selected attachment means. From the mounting base 26,the cannula extends angularly downwardly with its first portion nestedwithin the insertion needle 14, terminating slightly before the needletip 38. One or more apertures 19 are formed in the cannula 15 near thedistal segment end 16, in general alignment with the sensor electrodes18, to permit direct electrode exposure to patient body fluid when thesensor is transcutaneously placed.

In use, the insertion set 10 permits quick and easy transcutaneousplacement of the sensor distal segment 16 at a selected site within thebody of the patient. More specifically, the peel-off strip 28 is removedfrom the mounting base 26, at which time the mounting base 26 can bepressed onto and seated upon the patient's skin. During this step, theinsertion needle 14 pierces the patient's skin and carries theprotective cannula 15 with the sensor distal segment 16 therein to theappropriate transcutaneous placement site. During insertion, the cannula15 provides a stable support and guide structure to carry the flexiblesensor to the desired insertion site.

When the sensor 12 is transcutaneously placed, with the mounting base 26seated upon the patient's skin, the insertion needle 14 can be slidablywithdrawn from the patient. The slotted needle geometry permits theinsertion needle 14 to slide over and longitudinally separate from thesecond portion of the cannula 15, thereby leaving the cannula 15 as wellas the sensor distal segment 16 with electrodes 18 at the selectedinsertion site. These electrodes 18 are directly exposed to patient bodyfluid via the apertures 19. The sensor proximal segment 20 isappropriately coupled to the monitor 22, so that the sensor 12 can thenbe used over a prolonged period of time for taking blood chemistryreadings, such as BG readings in a diabetic patient. In an embodiment,when the insertion needle is withdrawn, a protective sheath (not shown)contained in the mounting base is dislodged and covers the needle tip asthe needle is separated from the mounting base. If desired, the cannula15 can also be used to deliver medication and/or sensor calibrationfluid to the vicinity of the electrodes 18, or alternately to withdrawpatient fluid such as blood for analysis.

While the description above refers to particular embodiments of thepresent invention, it will be understood that many modifications may bemade without departing from the spirit thereof. The accompanying claimsare intended to cover such modifications as would fall within the truescope and spirit of the present invention.

The presently disclosed embodiments are, therefore, to be considered inall respects as illustrative and not restrictive, the scope of theinvention being indicated by the appended claims rather than theforegoing description. All changes that come within the meaning of andrange of equivalency of the claims are intended to be embraced therein.

EXAMPLES

The examples set forth below are illustrative of different compositionsand conditions that can be used in practicing the invention. Allproportions are by weight unless otherwise indicated. It will beapparent, however, that the invention can be practiced with many typesof compositions and can have many different uses in accordance with thedisclosure above and as pointed out hereinafter.

Example I Step 1: Counter Electrode Metallization Step

A KAPTON® polyimide base is used as a base layer and spin coated on arigid substrate, such as glass. The first metallization comprisedsputter-based chrome, gold and top-chrome. The top chrome pattern wasphotoresisted using photomask to protect the metallized trace andcounter electrode. The uncovered areas of the base-chrome and gold wereetched. The etching was performed at 50° C. for the gold and at ambienttemperature for the chrome. The strip photoresisting was performed inisopropyl alcohol (“IPA”) at ambient temperature, and then again on allareas except the counter electrode, bond pad, and plating pad, atambient temperature. A second etching was then performed on thetop-chrome of all uncovered areas at ambient temperature. Stripphotoresisting was performed again in IPA at ambient temperature.Polyimide was spin coated on as an insulative layer. Photoimaging wasthen performed to cure specific areas. The resulting electrode layer wasdeveloped and rinsed.

Step 2: Working Electrode Metallization Step

The next electrode layer is formed generally above the counter electrodelayer. This second metallization step involves the same sputterbase-chrome and gold as a base layer. Photoresisting is performed usingphotomask to protect the working metallized trace and working electrodebeing formed. Etch is performed on the uncovered areas at 50° C. for thegold and at ambient temperature for the chrome. Strip photoresisting isagain performed in WA at ambient temperature. Next, photoresisting isperformed on all areas except the counter electrode, bond pad, andplating pad. Etching is performed on all uncovered areas of thetop-chrome at ambient temperature. Strip photoresisting is performed inIPA at ambient temperature. Polyimide was spin coated on as aninsulative layer. Photoimaging was then performed to cure specificareas. The resulting electrode layer was developed and rinsed.

Step 3: Reference Electrode Metallization Step

The next electrode layer is formed generally above the counter electrodelayer. This third metallization step also involves the sputterbase-chrome and gold combination as a base layer. Photoresisting isperformed using photomask to protect the working metallized trace andworking electrode being formed. Etch is performed on the uncovered areasat 50° C. for the gold and at ambient temperature for the chrome. Stripphotoresisting is again performed in WA at ambient temperature. Next,photoresisting is performed on all areas except the counter electrode,bond pad, and plating pad. Etching is performed on all uncovered areasof the top-chrome at ambient temperature. Strip photoresisting isperformed in IPA at ambient temperature. Polyimide was spin coated on asan insulative layer. Photoimaging was then performed to cure specificareas. The resulting electrode layer was developed and rinsed. After allthree electrode layers are formed, the layers are subjected to a finalbake at a high temperature, such as 325° C.

1. A method of making a flexible analyte sensor, the method comprising:providing a base layer; forming a first electrode layer on the baselayer, wherein the first electrode layer includes a first electrode;forming a first insulative layer on the first electrode layer, saidfirst insulative layer having opposed first and second longitudinalends; forming a first aperture in the first insulative layer to exposeat least a portion of the first electrode, said first aperture beingdisposed longitudinally between, and away from, said first and secondlongitudinal ends of the first insulative layer; forming a secondelectrode layer on the first insulative layer, wherein the secondelectrode layer includes a second electrode; forming a second insulativelayer on the second electrode layer, said second insulative layer havingopposed first and second longitudinal ends; and forming a secondaperture in the second insulative layer to expose at least a portion ofthe second electrode, said second aperture being disposed longitudinallybetween, and away from, said first and second longitudinal ends of thesecond insulative layer.
 2. The method of claim 1, wherein the maximumheight of the sensor is about 25 microns.
 3. The method of claim 1,wherein the providing a base layer includes spin coating polyimide ontoa rigid substrate.
 4. The method of claim 1, wherein the forming a firstelectrode layer includes surface sputtering a chrome-based layer on thebase layer.
 5. The method of claim 4, wherein the forming a firstelectrode layer further includes surface sputtering a gold-based layeron the chrome-based layer.
 6. The method of claim 1, wherein the forminga first insulative layer includes spin-coating polyimide onto the secondelectrode layer.
 7. The method of claim 1, wherein the first and secondapertures are formed by a photoresist process.
 8. The method of claim 1,further comprising depositing platinum black on one or more of the firstand second electrodes.
 9. The method of claim 1, further comprising:forming a third electrode layer on the second insulative layer, whereinthe third electrode layer includes a third electrode; forming a thirdinsulative layer above the third electrode layer, said third insulativelayer having opposed first and second longitudinal ends; and forming athird aperture in the third insulative layer to expose at least aportion of the third electrode, said third aperture being disposedlongitudinally between, and away from, said first and secondlongitudinal ends of the third insulative layer.
 10. The method of claim9, further comprising depositing one or more compounds selected from thegroup consisting of silver and silver chloride on the third electrode.11. The method of claim 10, further comprising coating at least aportion of the first electrode and the second electrode with an enzymelayer including glucose oxidase.
 12. The method of claim 11, furthercomprising vapor cross-linking the enzyme layer.
 13. The method of claim11, wherein the enzyme layer further includes albumin.
 14. The method ofclaim 11, further comprising forming an adhesion promoter layer abovethe enzyme layer.
 15. The method of claim 11, further comprising forminga glucose limiting membrane over the enzyme layer.
 16. The method ofclaim 15, wherein the glucose limiting membrane comprises at least oneof a silane and polyamine.
 17. The method of claim 15, furthercomprising forming a hydrophilic layer over the glucose limitingmembrane.
 18. The method of claim 9, wherein the first, second, andthird electrodes are in a staggered configuration.
 19. The method ofclaim 18, wherein the third electrode layer is disposed directly abovethe second electrode layer, and the second electrode layer is disposeddirectly above the first electrode layer.
 20. The method of claim 18,wherein the third electrode layer is laterally offset from the secondelectrode layer, and the second electrode layer is laterally offset fromthe first electrode layer.
 21. The method of claim 9, wherein one of theelectrodes is a counter electrode, one of the electrodes is a referenceelectrode, and one of the electrodes is a working electrode.
 22. Themethod of claim 9, wherein the first insulative layer is disposeddirectly on the first electrode layer without any intervening layers.23. The method of claim 9, wherein the second electrode layer isdisposed directly on the first insulative layer without any interveninglayers.
 24. The method of claim 9, wherein the second insulative layeris disposed directly on the second electrode layer without anyintervening layers.
 25. The method of claim 9, wherein the thirdelectrode layer is disposed directly on the second insulative layerwithout any intervening layers.
 26. The method of claim 9, wherein thethird insulative layer is disposed directly on the third electrode layerwithout any intervening layers.
 27. The method of claim 9, wherein theforming the first electrode layer further includes forming a firstconductive trace leading from the first electrode to a first conductivepad configured to electrically connect to sensor electronics, theforming the second electrode layer further includes forming a secondconductive trace leading from the second electrode to a secondconductive pad configured to electrically connect to sensor electronics,and the forming the third electrode layer further includes forming athird conductive trace leading from the third electrode to a thirdconductive pad configured to electrically connect to sensor electronics.28. The method of claim 27, wherein the sensor electronics communicatewirelessly with a monitor.